Under the guidance of her mentor, Dr. Heber Nielson, Dr. Volpe has developed independent research hypotheses addressing the role of Hox genes in normal and abnormal development. Her past studies have provided the focus for this current application. Dr. Volpe's immediate career goals involve establishing a career combining basic cell and molecular research in developmental lung biology with clinical care of premature infants (neonatology). This will be accomplished by further development and progress on the experiments she has outlined in this proposal. With the development of expertise and fostering of research collaborations in developmental and molecular biology, she is now at a point in her research career when focused time and effort in bench research and intensive educational studies in molecular biology and developmental biology, she is now at a point in her research career when focused time and effort in bench research and intensive educational studies in through this award will allow her to achieve these goals. Towards this purpose, Dr. Volpe will have Dr. Heber Nielson as he primary mentor, Dr. John Castellot as co-mentor, with advisory consultant support from Dr. Wellington Cardoso and Dr. Mala Chinoy. Hypothesis: Hoxb-5 affects lung patterning during branching morphogenesis through coordination of local morphogenetic signals. This hypothesis will be addressed by the following three Specific Aims. Specific Aim #1: Test to remodel airway patterning during branching morphogenesis. Specific Aim #2: Test the hypothesis that Hoxb-5 coordinates regional changes in morphogenetic signals during airway patterning through control of local cell-cell contacts and extracellular matrix (ECM) composition. Specific Aim #3: Test the hypothesis that Hoxb-5 regulates the interactive tension between retinoic acid and fibroblast growth factor 10 (FGF-10) to establish airway patterning during lung morphogenesis. The proposed research studies testing these hypothesis will further the understanding of the molecular mechanisms involved in normal lung development and ultimately aid in the creation of new strategies to treat neonatal lung diseases.